title: Regorafenib effects on human colon carcinoma xenografts monitored by dynamic contrast-enhanced computed tomography with immunohistochemical validation.
abstract: OBJECTIVE
  To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.
  
  
  METHODS
  Colon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67).
  
  
  RESULTS
  Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = -0.66 and -0.71).
  
  
  CONCLUSIONS
  Regorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.
authors.affiliation: Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Grosshadern Campus, Muenchen, Germany.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Kazmierczak
authors.forename: Heidrun
authors.initials: H
authors.lastname: Hirner
authors.forename: Matthias
authors.initials: M
authors.lastname: Moser
authors.forename: Michael
authors.initials: M
authors.lastname: Ingrisch
authors.forename: Lukas
authors.initials: L
authors.lastname: Havla
authors.forename: Alexandra
authors.initials: A
authors.lastname: Michels
authors.forename: Ralf
authors.initials: R
authors.lastname: Eschbach
authors.forename: Bettina
authors.initials: B
authors.lastname: Schwarz
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D064593:Heterografts / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008833:Microcirculation / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib